Welches (ist das richtige) Target bei nichtalkoholischer Fettleber (NAFLD)

Zusammenfassung

Die nichtalkoholische Fettleber (NAFLD) ist die am stärksten zunehmende Lebererkrankung weltweit. Vielen Patienten gelingt es nicht, durch eine Änderung des Lebensstils einen positiven Einfluss auf die Erkrankung zu erzielen, und der Bedarf an einer pharmakologischen Therapie in dieser Gruppe ist hoch. In Analogie zu anderen metabolischen Erkrankungen wie z. B. dem Diabetes mellitus Typ 2 oder Fettstoffwechselstörungen wird vermutlich ein großer Teil von Patienten eine dauerhafte medikamentöse Therapie benötigten. Derzeit sind mehrere Substanzen mit verschiedenen pathophysiologischen Ansätzen in klinischer Testung. Dabei können metabolische, antiinflammatorische und antifibrotische Wirkmechanismen unterschieden werden. Mehrere Substanzen befinden sich bereits in Phase-3-Studien. Dazu zählen Elafibranor (PPAR-α/δ-Agonist), Cenicriviroc (CCR2/CCR5-Inhibitor), Obeticholsäure (FXR-Agonist), Aramchol (SCD1-Modulator) und Resmetrion (Thyroid-Hormon-Rezeptor-beta-Agonist). Weitere Studien mit pathophysiologisch vielversprechenden Wirkmechanismen, z. B. dem ASK-1-Inhibitor Selonsertib oder dem Caspase-Inhibitor Emricasan, haben bislang negative Ergebnisse gezeigt, werden jedoch z. T. in Kombinationstherapien weiter evaluiert. Die komplexe Pathophysiologie der Erkrankung, die Entzündung, Stoffwechsel und Fibrose verknüpft, hat dazu geführt, dass auch Kombinationen mehrerer Substanzen mit verschiedenen Wirkansätzen untersucht werden. Die vorliegende Übersicht fasst die Ende 2019 in klinischen Studien der Phase 3 befindlichen Substanzen für Patienten mit NASH ohne Leberzirrhose zusammen.

Abstract

Non-alcoholic fatty liver disease (NAFLD) is of increasing prevalence globally. While lifestyle modifications are recommended, many patients do not succeed to achieve significant and maintained weight loss from lifestyle and as such there is a high unmet need for pharmacotherapy in this group. Comparable to other metabolic diseases including diabetes and dyslipidaemia, a high proportion of patients will likely benefit from permanent pharmacological therapy. Currently there are many compounds with different mechanisms of action in clinical development including metabolic, anti-inflammatory and anti-fibrotic drugs. A number of phase 3 clinical trials are currently ongoing including Elafibranor, a dual PPAR α/δ agonist, Cenicriviroc, a CCR2/CCR5 chemokine antagonist, the nuclear bile acid receptor FXR agonist obeticholic acid, Aramchol, a fatty acid bile acid conjugate that modulates SCD-1, and Resmetrion, a liver-specific THR-β agonist. Further studies with promising pathophysiological mechanisms of action, e. g. the ASK-1 inhibitor Selonsertib or the caspase inhibitor Emricasan have shown negative results. However, some are being further evaluated in combination therapies. The complex pathophysiology of the disease, which combines inflammation, metabolism and fibrosis, has led to the fact that even combinations of several substances are investigated with different modes of action. This review summarizes pivotal clinical trials for patients with NASH in the absence of cirrhosis which are recruiting in the fall of 2019.

Schlüsselwörter

Leber - Therapie - Phase 2 - Phase 3 - Medikamente

Key words

NAFLD - NASH - therapy - phase 2 - phase 3 - clinical trials

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